LRBA organizes distinct vesicular trafficking systems in distal nephron segments for water and sodium conservation
Abstract
Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is a rare genetic disorder characterized by immune dysregulation. The immune checkpoint molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) fails to perform proper membrane trafficking in the absence of LRBA. In addition to immune cells, LRBA localizes to intracellular vesicles in various epithelial cells; however, its physiological roles have not been accurately deciphered. It was observed in this study that LRBA facilitates water and sodium transport by promoting vesicular trafficking of aquaporin-2 (AQP2) and AQP4 in renal collecting duct cells and that of sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) in distal convoluted tubule cells. Consequently, Lrba knockout mice exhibited vasopressin-resistant polyuria and hypotension under sodium-restricted conditions. This registry study revealed a polyuric phenotype in a subset of patients with LRBA deficiency, characterized by inappropriately low urine specific gravity despite the presence of chronic diarrhea. Notably, desmopressin treatment ameliorated impaired urinary concentration in a mouse model of human LRBA deficiency. LRBA functions as a central coordinator of fluid and sodium homeostasis by organizing segment-specific vesicular trafficking systems in renal epithelial cells.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Kanako Nagaoka
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Fumiaki Ando
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Tamami Fujiki
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Hassan Abolhassani
Yu Hara
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Hideki Yanagawa
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Soichiro Suzuki
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Yuriko Sakamaki
Ochanomizu Research Facility, Bioscience Center, Institute of Science Tokyo
Daisuke Oikawa
Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University
Hiroaki Kikuchi
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Shintaro Mandai
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Yutaro Mori
Department of Chemical Science and Engineering, Graduate School of Engineering
Takayasu Mori
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Koichiro Susa
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Eisei Sohara
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Akihiro Hoshino
Department of Child Health and Development, Institute of Science Tokyo
Tsuyoshi Ito
Department of Pediatrics, Toyohashi Municipal Hospital
Yuki Arakawa
Department of Hematology/Oncology, Saitama Children’s Medical Center
Yoji Sasahara
Department of Pediatrics, Tohoku University Graduate School of Medicine
Shinsuke Yasuda
Department of Rheumatology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
Yoichiro Abe
Department of Pharmacology, Keio University School of Medicine
Masato Yasui
Department of Pharmacology, Keio University School of Medicine
Fuminori Tokunaga
Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University
Hirokazu Kanegane
Department of Child Health and Development, Institute of Science Tokyo
Shinichi Uchida
Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo